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Antinuclear Autoantibodies in Health: Autoimmunity Is Not a Synonym of Autoimmune Disease

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Antinuclear Autoantibodies in Health: Autoimmunity Is Not a Synonym of Autoimmune Disease antibodies Review Antinuclear Autoantibodies in Health: Autoimmunity Is Not a Synonym of Autoimmune Disease Irina A. Pashnina 1,*, Irina M. Krivolapova 1,2, Tamara V. Fedotkina 3, Varvara A. Ryabkova 3 , Margarita V. Chereshneva 2, Leonid P. Churilov 3,4 and Valeriy A. Chereshnev 2 1 Regional Children’s Clinical Hospital, 620149 Yekaterinburg, Russia; [email protected] 2 Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, 620049 Yekaterinburg, Russia; [email protected] (M.V.C.); [email protected] (V.A.C.) 3 Laboratory of the Mosaics of Autoimmunity, Saint Petersburg State University, 199034 Saint Petersburg, Russia; [email protected] (T.V.F.); [email protected] (V.A.R.); [email protected] (L.P.C.) 4 Saint Petersburg Research Institute of Phthisiopulmonology, 191036 Saint Petersburg, Russia * Correspondence: [email protected] Abstract: The incidence of autoimmune diseases is increasing. Antinuclear antibody (ANA) testing is a critical tool for their diagnosis. However, ANA prevalence in healthy persons has increased over the last decades, especially among young people. ANA in health occurs in low concentrations, with a prevalence up to 50% in some populations, which demands a cutoff revision. This review deals with the origin and probable physiological or compensatory function of ANA in health, according to the concept of immunological clearance, theory of autoimmune regulation of cell functions, and the concept of functional autoantibodies. Considering ANA titers ≤1:320 as a serological marker of Citation: Pashnina, I.A.; autoimmune diseases seems inappropriate. The role of anti-DFS70/LEDGFp75 autoantibodies is Krivolapova, I.M.; Fedotkina, T.V.; highlighted as a possible anti-risk biomarker for autoimmune rheumatic disorders. ANA prevalence Ryabkova, V.A.; Chereshneva, M.V.; in health is different in various regions due to several underlying causes discussed in the review, Churilov, L.P.; Chereshnev, V.A. Antinuclear Autoantibodies in Health: all influencing additive combinations according to the concept of the mosaic of autoimmunity. Autoimmunity Is Not a Synonym of Not only are titers, but also HEp-2 IFA) staining patterns, such as AC-2, important. Accepting Autoimmune Disease. Antibodies autoantibodies as a kind of bioregulator, not only the upper, but also the lower borders of their normal 2021, 10, 9. https://doi.org/ range should be determined; not only their excess, but also a lack of them or “autoimmunodeficiency” 10.3390/antib10010009 could be the reason for disorders. Academic Editors: Gregory Keywords: autoimmune diseases; antinuclear antibodies; antinuclear factor; functional autoantibodies; C. Ippolito and Jagadeesh Bayry natural autoantibodies; physiological autoimmunity Received: 27 October 2020 Accepted: 7 February 2021 Published: 25 February 2021 1. Introduction The incidence of autoimmune diseases (ADs) is high worldwide among both adults Publisher’s Note: MDPI stays neutral and children. According to various estimates, the total incidence of ADs in different coun- with regard to jurisdictional claims in published maps and institutional affil- tries and regions varies from 5% to almost 30%, and there is an annual increase [1–5]. iations. This is particularly the case for systemic ADs with non-organ-specific autoantibodies [1]. ADs significantly impair the quality of life of patients and often lead to severe, usually lifelong disability. They require significant costs from the health care system when diag- nosed at late stages: for example, the annual costs of treating one case of systemic lupus erythematosus (SLE) with renal or neuropsychiatric complications in the USA in 2013 Copyright: © 2021 by the authors. exceeded 30,000–32,000 US $, being 6.25–6.5 times higher than the cost of treating the initial, Licensee MDPI, Basel, Switzerland. inactive, and uncomplicated phases of the disease [6]. Early diagnosis of ADs is desirable, This article is an open access article distributed under the terms and but the process often takes a long time, due to the absence of specific symptoms in early conditions of the Creative Commons stages of these diseases in many patients [7–10]. This factor determines the relevance of the Attribution (CC BY) license (https:// search for laboratory tests suitable for the early diagnosis and screening of ADs in order to creativecommons.org/licenses/by/ timely prescribe appropriate treatment. 4.0/). Antibodies 2021, 10, 9. https://doi.org/10.3390/antib10010009 https://www.mdpi.com/journal/antibodies Antibodies 2021, 10, 9 2 of 26 Identification of different autoantibodies is used for the diagnosis of ADs [11,12]. Some of them are associated with specific autoimmune diseases [10,13–15]. However, the reliability of autoantibodies as pathognomonic markers of a particular disease is far from 100%; moreover, many of them are observed in several different nosological entities. Their association with a certain disease sometimes requires confirmation of antigenic specificity by several different methods; therefore, the general consensus is that the term “disease associations” should be replaced by “clinical relevance” of the identified autoantibodies [16]. In addition, there is a growing body of evidence that the responsibility of the immune system is not only (and even not mainly) the protection against foreign intrusions. The im- mune system serves as a physiological sensory and analytical instrument in relation to the antigenic structure of the multicellular organism, responsible for its maintenance and even its formation. Therefore, auto-recognition is regarded as a normal primary function of the immune system, which is associated with the existence of physiological autoimmunity [17,18]. In this review, we address the issue of antinuclear antibody (ANA) testing, which has been detected by indirect immunofluorescence and known since 1958 under the traditional name “antinuclear factor” (ANF) [19]. We discuss the ANA presence and role in healthy individuals, the peculiarities of distinguishing between normal and pathological positive ANA-test results, the role of ontogenetic and geographical factors in ANA prevalence—in the context of the concept of physiological autoimmunity—and its relationship with ADs. 2. Physiological Autoimmunity and Its Bidirectional Pathological Changes Almost all autoantibodies, including ANA, are often found not only in the sera of patients who suffer from ADs, but also in healthy persons (including those who do not develop a disease during follow-up), although in health, low titers of autoantibodies are usually found [19–22]. The issue of natural autoantibodies and physiological autoimmunity has acquired considerable relevance with the development of more sensitive laboratory tests, because autoantibodies to many antigens, including cell nuclei and membrane receptors, have be- come routinely registered in the blood and mucous secretions of healthy people with these methods [23–29]. This is also true for the autoantibodies that are considered typical markers of certain ADs, for example, IgG against the glomerular basement membrane, proteinase 3, myeloperoxidase, myelin basic protein, etc. [30,31]. Moreover, due to the presence of both agonistic and antagonistic effects of such autoanti- bodies of healthy donors on the receptors of neurotransmitters [32,33], hormones [34,35], auta- coids [36,37], and IgE [38], the question of their possible physiological regulatory role has long been raised. Indeed, there is growing evidence for this aspect of physiological autoimmunity [39–42]. 2.1. Physiological Autoimmunity: Historical Perspective and Contemporary Understanding In accordance with the assumption of the possible regulatory role of autoimmunity, several fruitful scientific doctrines have been formulated in different periods, rooted in the ideas of I.I. Mechnikov, who considered the immune system as a means of forming and maintaining the multicellularity of the metazoan organism [43]. These doctrines are: the doctrine of cytotoxins, the theory of autoimmune regulation of cellular functions, and the theory of immunological clearance [39,41,44,45]. The term “functional autoantibodies” (which primarily relates to the autoantibodies against plasma membrane receptors) was coined in recent years and indicates the modern version of the mentioned ideas [32,46,47]. However, with regard to the functional properties, ANAs cannot be considered an exception, since it was shown in vivo and in vitro that ANAs can penetrate not only into the cytoplasm, but also into the nuclei of living cells (moreover, this occurs with the involvement of antigen binding sites). ANAs can influence gene expression, cell growth, and apoptosis. Therefore, not only regulation, mediated by membrane receptors, but also repression/activation of genes through cis-regulatory elements of chromatin can be carried out by autoimmune mechanisms [44,48–52]. Antibodies 2021, 10, 9 3 of 26 It is no coincidence that there is a growing number of studies which showed that: 1. Patients with certain ADs show a decrease in the level of certain autoantibodies and/or the strength of antibody-mediated bioeffects in comparison with healthy donors; 2. The level of autoantibodies decreases, rather than increases during exacerbations of some ADs; 3. Some autoantibodies are associated with a favorable outcome of the disease. This was demonstrated both for the autoantibodies to cell surface receptors [42,53–56] and for ANA [12,57]. For example, anti-DFS70 autoantibodies against
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